The field of the invention is improved polyurethane compositions for in vitro and in vivo use, including calcification-resistant, thrombogenesis-resistant, and degradation-resistant polyurethanes.
Polyurethanes are polymers which can be made by condensing a diisocyanate with a diol, with two or more diols having different structures, or with both a diol and a diamine. For example, polyurethanes can be made as illustrated in FIGS. 1A and 1B. In FIG. 1A, a diisocyanate (OCN--A--CNO) is reacted with a diol (HO--X--OH) to form a polyurethane. It is understood that the proportion of end groups corresponding to the diisocyanate and the diol can be controlled by using an excess of the desired end group. For example, if the reaction in FIG. 1A is performed in the presence of an excess of the diisocyanate, then the resulting polyurethane will have isocyanate (--NCO) groups at each end.
Depending on the identity of the reaction products used to from them, polyurethanes can behave as elastomers or as rigid, hard thermosets. If the diisocyanate depicted in FIG. 1A is, for example, 4,4'-methylenebis(phenylisocyanate), which has the following structure ##STR1##
then the region designated "HS" (i.e., `hard segment`) in FIG. 1A will be relatively inflexible. If the diol depicted in FIG. 1A is, for example, polytetramethyleneoxide (i.e., HO--(CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 O).sub.k --H, wherein, e.g., k is about 10 to 30), then the region designated "SS" (i.e., `soft segment`) will be relatively flexible. Methods of selecting polyurethane precursors which will yield a polyurethane having hard and soft segments which confer a desired property (e.g., flexibility, elastomericity, etc.) to the polyurethane are well known in the art.
As illustrated in FIG. 1B, methods of making segmented polyurethanes are also known in the art. In these methods, one or more types of polyurethane precursors (OCN--P--NCO) are reacted with a chain extending compound (HZ--Y--ZH) to yield a segmented polyurethane. By varying the proportions of different types of polyurethane precursors, their end groups, the identity of the chain extender, and the like, the composition of polyurethane segments in the segmented polymer can be controlled, as is known in the art.
Medical grade segmented polyurethanes are usually prepared as depicted in FIGS. 1A and 1B, by condensing a diisocyanate with a polymeric diol having a molecular weight of about 1,000 to 3,000 (e.g., polytetramethyleneoxide for polyether-urethanes or polycarbonatediols for polycarbonate-urethanes) in order to form a polyurethane precursor which is subsequently reacted with an approximately equivalent amount of a chain extender (e.g., a diol such as 1,4-butanediol or a diamine such as a mixture of diaminocyclohexane isomers).
Polyurethanes can be used to form bulk polymers, coatings, fillings, and films. They are also readily machinable once set. The properties of polyurethanes have rendered them useful for medical and non-medical purposes, and they have been used for such purposes since at least the beginning of the twentieth century. Medical uses of polyurethanes have, however, been heretofore limited by the tendency of polyurethane products which contact the blood stream or other biological fluids to calcify, induce thrombogenesis, and/or chemically and mechanically deteriorate. It is believed that polyurethane deterioration results, at least in part, from chemical breakdown of the block-copolymer structure of the polyurethane molecule.
Prior art methods of improving polyurethane stability have relied primarily upon two approaches. One approach involves incorporation into the polyurethane backbone of chain extending compound having groups to which substituents can be added. For example, condensation of the di-hydroxy compound 1,2-di-hydroxy-1,2-bis(diethoxyphosphinyl)ethane with diisocyanates yields a polyurethane having reduced flammability and having esterified phosphonic groups attached to the polymer backbone, as described (Mikroyannidis, 1984, J. Polymer Sci., Polymer Chem. Ed. 22:891-903). These polymers have potential drawbacks when used in biomedical applications because of reduced reactivity of the di-hydroxy chain extending compounds, relative to standard chain-extenders such as 1,4-butanediol. Thus, the molecular weight and mechanical properties of polymers modified in this manner may preclude their medical use.
Chain extending compounds having quaternary ammonium and phosphorylcholine groups have been used to prepare polyurethanes for medical purposes (Baumgartner et al., 1996, ASAIO J. 42:M476-M479). However it does not appear to be possible to insert non-esterified phosphonic groups into polyurethanes using 1,2-diols having such groups, presumably because of the ability of phosphonic hydroxyl groups to react with isocyanates. At the same time, cleavage of phosphonic esters attached to the backbone of the polymer would result in simultaneous cleavage of urethane bonds.
The second approach to stabilizing polyurethanes is based on N-alkylation of urethane amine groups of the polyurethane chain. Contacting a polyurethane with an alkylating; agent in the presence of a strong base results in alkylation of the urethane amine groups of the chain to yield additionally-substituted amine groups. It is believed that the strong base serves to extract protons from the urethane nitrogen. It has been demonstrated that moderate grades of metallation with sodium hydride at temperatures not significantly exceeding 0.degree. C. do not induce significant polymer degradation (Adibi et al., 1979, Polymer 20:483-487). The polyanions remain soluble in aprotic solvents like dimethyl formamide and N,N-dimethylacetamide (DMA).
The first application of this N-alkylation method to medical grade polyurethanes involved N-alkylation of sodium hydride-activated polymer using alkyl iodides to attach C.sub.2 to C.sub.18 alkyl chains to the polymer backbone (Grasel et al., 1987, J. Biomed. Mat. Res. 21:815-842). It is believed that addition of such alkyl chains to polyurethanes improves the blood compatibility of the polymers. Grasel et al. pre-treated the polyurethane with sodium hydride at a temperature of from -5.degree. C. to 0.degree. C., and the reaction of the activated polymer with alkyl iodides was performed at a temperature of about 50.degree. C. At this temperature, degradation of the polymer chain can occur. Further developments of such methods allowed substitution of the polymer chain with 3-carboxypropyl and 3-sulfonopropyl groups by activating the polyurethane chain using sodium hydride and then alkylating the chain using sodium salts of 4-iodobutyric acid or 1,3-propane sultone. Preparation of 3-carboxypropyl-modified polymers was complicated by the relatively low solubility of sodium 4-iodobutyrate in DMA. Another drawback to this method is that 4-iodobutyric acid, and alkyl iodides in general, are expensive and are not sufficiently stable in storage.
A need exists for methods of making improved polyurethane compositions which do not exhibit the utility-limiting effects exhibited by prior art polyurethanes. The present invention satisfies this need by providing polyurethane compositions which exhibit reduced thrombogenesis, reduced calcification, and greater resistance to chemical and mechanical deterioration.